Acne is a disease of the skin in which the pilosebaceous structures of the skin become inflamed, leading to the formation of comedones, pustules and nodules. It is generally believed that acne arises when hyperkeratosis of the pilosebaceous structure wholly or partially blocks the opening of the structure, resulting in comedones filled with sebum, keratin, and Propionibacterium acnes (“P. acnes”). These lesions are commonly identified as acne. P. acnes naturally occurs in normal skin, but is especially and characteristically present in acne lesions. It is believed that metabolic byproducts and waste from P. acnes within the pilosebaceous structures cause or contribute to the inflammation of acne lesions.
Acne naturally varies in severity from mild to very severe. People with mild (superficial) acne develop only a few noninflamed blackheads or a moderate number of small, mildly irritated pimples, mostly on the face. Blackheads appear as tiny, dark dots at the center of a small swelling of normal-colored skin. Pimples are mildly uncomfortable and have a white center surrounded by a small area of reddened skin. People with severe (deep, or cystic) acne, on the other side, have numerous large, red, painful pus-filled lumps (nodules) that sometimes even join together under the skin into giant, oozing abscesses.
Depending on the degree of severity and pronounced appearance, one speaks of acne vulgaris, acne comedonica, acne papulo pustulosa, acne conglobata, etc. Further, the acne can be subdivided into two categories, inflammatory acne and non-inflammatory acne, based on both pathophysiological and therapeutic differences.
Conventional acne treatments have taken many forms. Oral drugs including antibiotics like tetracycline, minocycline, doxycycline, and erythromycin, and topical keratolytic agents, such as salicylic acid are sometimes used. Keratolytic agents are thought to encourage the opening up of blocked pilosebaceous structures, thereby reducing conditions that are favorable to inflammation. Benzoyl peroxide, an anti-microbial, remains a popular and effective treatment. Topical antibiotics, such as clindamycin, which are effective against P. acnes, have also been used with a view towards preventing the formation of metabolic byproducts from this organism.
A treatment option for acne is retinoids, which have been widely described in the past for treatment of a number of dermatological disorders, including acne and seborrhoea. Orally administered 13-cis retinoic acid (isotretinoin) revolutionized the treatment of severe forms of acne when it was introduced in 1982, and continues in the present to be the single therapy capable of curing severe acne. Oral isotretinoin is so effective against acne because it is the only treatment affecting all major etiological factors, including, in particular, a substantial reduction of sebum production by inhibition of the lipogenesis, as well as a reduction of the size of sebaceous glands of the patient. Thus, oral isotretinoin was established in the last decade as the gold standard of acne therapy, capable of long-term remission in about 80% of patients with severe acne.
Retinoids are known to possibly cause several serious side-effects, in particular when administered systemically, like birth defects; mental health problems including suicide danger; uncontrolled increases of brain pressure which can, e.g., lead to permanent loss of sight; damage of liver, pancreas, bowel and esophagus; possible bone and muscle problems; development of high levels of cholesterol and other fats in the blood; and others. However, retinoid formulations when administered topically would certainly represent an improvement with regard to the risk of possible side effects because of the substantially shorter way of the drug from the point of administration to the point of action associated with topical administration that results in a lower systemic exposure; hence topical therapy may be preferable over oral retinoid therapy.
A number of topical retinoid formulations are commercially available in the form of creams, gels, lotions, ointments and solutions. However the available topical dosage forms have been reported to produce skin irritation (dermatitis) which may be characterized by erythema, scaling, peeling, drying, pruritus, and sensations similar to sunburn. This problem is described in U.S. Pat. No. 4,888,342. Other side effects have also been reported with topical retinoids like itching, stinging or burning. Rarely edema, and blistering or crusting of skin may occur. Temporary hypopigmentation or hyperpigmentation has been reported in a few individuals treated with tretinoin. Temporary depigmentation in non-Caucasians is possible.
Retinoids are insoluble or at most very slightly soluble in water, but readily soluble in, e.g., ethyl alcohol. Therefore retinoid containing preparations have been most effectively applied using an ethyl alcohol containing carrier system, which causes an uncomfortable burning sensation by itself. This sensation is amplified when applied to skin which was previously or is simultaneously treated with retinoic acid. Most of the topical retinoids formulations available in the market, like Isotrex® gel, Isotrexin® gel, Retin-A® (tretinoin) solution and Solage® (mequinol and tretinoin) solution contain ethyl alcohol.
WO 90/14833 discloses an aqueous composition for topical application to the skin, comprising a retinoid with ethyl alcohol and surfactant. Said composition comprises 0.1 to 20 wt % of a solubilizing agent (ethyl alcohol) and a surfactant.
Most of the prior art discloses the use of an additional agent to reduce the skin irritation caused by formulations containing anti acne agent. These additional agents add an unnecessary load to the formulation.
U.S. Pat. No. 5,252,604 discloses the use of tocopherol such as alpha tocopherol in the topical composition of retinoic acid to overcome the problem of retinoic acid induced dermatitis resulting from topical retinoic acid application as tocopherol has free radical scavenging antioxidant properties.
U.S. Pat. No. 4,593,046 discloses a method of reducing skin irritation from benzoyl peroxide by the use of aloe vera which helps to reduce specific undesirable reactions which would otherwise result from the use of benzoyl peroxide to treat skin lesions.
U.S. Pat. No. 6,277,881 discloses the use of turmeric extract as an anti-irritant/anti-sting agent in the compositions containing hydroxy acids and/or retinoids.
U.S. Pat. No. 5,643,584 discloses a retinoid aqueous gel composition having effective amount of micronized retinoid particles, a surfactant to enhance penetration of retinoid into the skin, a preservative and a gelling agent. The invention also included polyvinylpyrrolidone to inhibit crystal growth of the micronized retinoids.
Cream formulations were found to be generally more acceptable to patients, but they were not without disadvantages, such as a reduced clinical effectiveness as compared with alcoholic compositions containing the same amount of retinoic acid. Aqueous retinoic acid preparations containing no alcohol and no fats have not shown to be clinically very effective, due to the fact that the active ingredient is not dissolved and, thus, not available for exerting the desired effect.
Thus, there exists a need for a composition comprising a retinoid, which is chemically and physically stable, that is completely or substantially free of ethyl alcohol and surfactant-free, yet is able to provide solubilized retinoid immediately and is clinically effective as a prior art compositions, with minimal or no skin irritation. The present invention provides such a retinoid composition.